The present invention is concerned with novel 1,8-annelated 2-quinolinone derivatives, the preparation thereof, pharmaceutical compositions comprising said novel compounds and the use of these compounds as a medicine as well as methods of treatment by administering said compounds.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer. A particular group of oncogenes is known as ras which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian ras oncogenes consists of three major members (xe2x80x9cisoformsxe2x80x9d): H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highly related proteins generically known as p21ras. Once attached to plasma membranes, the mutant or oncogenic forms of p21ras will provide a signal for the transformation and uncontrolled growth of malignant tumor cells. To acquire this transforming potential, the precursor of the p21ras oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, will prevent the membrane attachment of p21ras and block the aberrant growth of ras-transformed tumors. Hence, it is generally accepted in the art that farnesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contributes to transformation.
Since mutated oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has been suggested that farnesyl tranferase inhibitors can be very useful against these types of cancer.
In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substituted quinoline and quinolinone derivatives which suppress the plasma elimination of retinoic acids. Some of these compounds also have the ability to inhibit the formation of androgens from progestines and/or inhibit the action of the aromatase enzyme complex.
Unexpectedly, it has been found that the present novel compounds, all having a phenyl substituent on the 4-position of the 1,8-annelated 2-quinolinone-moiety bearing a nitrogen- or carbon-linked imidazole, show farnesyl protein transferase inhibiting activity.
The present invention concerns compounds of formula 
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
the dotted line represents an optional bond;
X is oxygen or sulfur;
xe2x80x94Axe2x80x94 is a bivalent radical of formula
xe2x80x83wherein optionally one hydrogen atom may be replaced by C1-4alkyl or Ar1;
R1 and R2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar2, Ar2xe2x80x94C1-6alkyl, Ar2-oxy, Ar2xe2x80x94C1-6alkyloxy; or when on adjacent positions R1 and R2 taken together may form a bivalent radical of formula
R3 and R4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar3-oxy, C1-6alkylthio, di(C1-6alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R3 and R4 taken together may form a bivalent radical of formula
R5 is a radical of formula 
xe2x80x83wherein
R13 is hydrogen, halo, Ar4, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R14 is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;
R6 is hydrogen, hydroxy, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar5, Ar5xe2x80x94C1-6alkyloxyC1-6alkyl; or a radical of formula
xe2x80x83wherein
R7 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar6, Ar6xe2x80x94C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula -Alk-OR10 or -Alk-NR11R12;
R8 is hydrogen, C1-6alkyl, Ar7 or Ar7xe2x80x94C1-6alkyl;
R9 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar8, Ar8xe2x80x94C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, Ar8-carbonyl, Ar8xe2x80x94C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical or formula -Alk-OR10 or -Alk-NR11R12;
wherein Alk is C1-6alkanediyl;
R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar9 or Ar9xe2x80x94C1-6alkyl;
R11 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar10 or Ar10xe2x80x94C1-6alkyl;
R12 is hydrogen, C1-6alkyl, Ar11 or Ar11xe2x80x94C1-6alkyl; and
Ar1 to Ar11 are each independently selected from phenyl; or phenyl substituted with halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.
R13 may also be bound to one of the nitrogen atoms in the imidazole ring of formula (d-1). In that case the meaning of R13 when bound to the nitrogen is limited to hydrogen, Ar4, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)xe2x80x94C1-6alkyl or C1-6alkylS(O)2C1-6alkyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C1-6alkyl includes C1-4alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C1-6alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof; C2-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like. The term xe2x80x9cS(O)xe2x80x9d refers to a sulfoxide and xe2x80x9cS(O)2xe2x80x9d to a sulfon.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The term acid addition salts also comprises the hydrates and the solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term stereochemically isomeric forms of compounds of formula (I), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Wherever xe2x80x94Axe2x80x94 is a bivalent radical of formula (a-4), (a-5), (a-6), (a-7) or (a-8) the CH2 or CH moiety in said bivalent radical is preferably connected to the nitrogen atom of the 2-quinolinone-moiety of the compounds of formula (I) or the intermediates of formula (II), (IV), (VI) and (VII).
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to include also the pharmaceutically acceptable acid addition salts and all stereoisomeric forms.
A group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply:
a) the dotted line represents an optional bond;
b) X is O or S;
c) R1 and R2 are each independently selected from hydrogen, halo, C1-6alkyl, C1-6alkyloxy, trihalomethyl or trihalomethoxy; in particular hydrogen, halo or C1-4alkyl;
d) R3 and R4 are each independently selected from hydrogen, halo, C1-6alkyl, C1-6alkyloxy, trihalomethyl or trihalomethoxy; in particular hydrogen, halo, C1-4alkyl or C1-4alkyloxy;
e) R5 is a radical of formula (d-1) wherein R13 is hydrogen or C1-6alkyl; or R5 is a radical of formula (d-2) wherein R13 is hydrogen or C1-6alkyl and R14 is hydrogen or C1-6alkyl;
f) R6 is hydrogen, hydroxy, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula xe2x80x94NR8R9 wherein R8 is hydrogen or C1-6alkyl and R9 is hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkylcarbonyl; in particular R6 is hydrogen, hydroxy, halo or a amino;
g) xe2x80x94Axe2x80x94 is (a-1), (a-2), (a-3), (a-4), (a-5), (a-8), (a-9) or (a-10).
A particular group of compounds consists of those compounds of formula (I) wherein the dotted line represents a bond; X is O or S; R2 is hydrogen and R1 is halo, preferably chloro, especially 3-chloro; R4 is hydrogen and R3 is halo, preferably chloro, especially 4-chloro; R5 is a radical of formula (d-1) wherein R13 is hydrogen or C1-4alkyl; and R6 is hydrogen.
Another particular group of compounds consists of those compounds of formula (I) wherein the dotted line represent a bond; X is O or S; R2 is hydrogen and R1 is halo, preferably chloro, especially 3-chloro; and R4 is hydrogen and R3 is halo, preferably chloro, especially 4-chloro; R5 is a radical of formula (d-2) wherein R13 is hydrogen or C1-4alkyl and R14 is hydrogen or C1-4alkyl; R6 is hydrogen, hydroxy, halo or amino.
Preferred compounds are those compounds of formula (I) wherein the dotted line represents a bond; X is oxygen; R1 is 3-chloro; R2 is hydrogen; R3 is 4-chloro; R4 is hydrogen; R5 is a radical of formula (d-1) wherein R13 is hydrogen or C1-4alkyl; R6 is hydrogen, and xe2x80x94Axe2x80x94 is (a-1), (a-2) or (a-3).
Other preferred compounds are those compounds of formula (I) wherein the dotted line represent a bond; X is oxygen; R1 is 3-chloro; R2 is hydrogen; R3 is 4-chloro; R4 is hydrogen; R5 is a radical of formula (d-2) wherein R13 is hydrogen and R14 is C1-4alkyl; R6 is amino; and xe2x80x94Axe2x80x94 is (a-1), (a-2) or (a-3).
The most preferred compounds of formula (I) are
7-(3-chlorophenyl)-9-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one,
7-(3-chlorophenyl)-9-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,
8-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, and
8-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3-chlorophenyl)-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one; the stereoisomeric forms and the pharmaceutically acceptable acid addition salts thereof.
The compounds of formula (I), wherein R6 is hydroxy and R5 is a radical of formula (d-2) wherein R14 is C1-6alkyl, said compounds being referred to as compounds of formula (I-a-1) may be prepared by reacting an intermediate ketone of formula (II) with a intermediate of formula (III-1). Said reaction requires the presence of a suitable strong base, such as, for example, butyl lithium in an appropriate solvent, such as, for example, tetrahydrofuran, and the presence of an appropriate silanederivative, such as, for example, triethylchlorosilane. During the work-up procedure an intermediate silane derivative is hydrolyzed. Other procedures with protective groups analogous to silanederivatives can also be applied. 
Also, the compounds of formula (I), wherein R6 is hydroxy and R5 is a radical of formula (d-2) wherein R14 is hydrogen, said compounds being referred to as compounds of formula (I-a-2) may be prepared by reacting an intermediate ketone of formula (II) with a intermediate of formula (III-2), wherein PG is a protective group such as, for example, a sulfonyl group, e.g. a dimethylamino sulfonyl group, which can be removed after the addition reaction. Said reaction is conducted analogously as for the preparation of compounds of formula (I-a-1), followed by removal of the protecting group PG, yielding compounds of formula (I-a-2).
Compounds of formula (I-g), defined as compounds of formula (I) wherein R5 represents a radical of formula (d-1), can be prepared by N-alkylating an intermediate of formula (XVIII) with an intermediate of formula (XVII), wherein W is an appropriate leaving group such as, for example, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy. The reaction can be performed in a reaction-inert solvent such as, for example, acetonitrile, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and the reflux temperature of the reaction mixture. 
Also, compounds of formula (I-g) can be prepared by N-alkylating an intermediate of formula (XIX), wherein Y is carbon or sulfur, such as, for example, a 1,1xe2x80x2-carbonyl-diimidazole, with an intermediate of formula (XVI). 
Said reaction may conveniently be conducted in a reaction-inert solvent, such as, e.g. tetrahydrofuran, optionally in the presence of a base, such as sodium hydride, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.
Compounds of formula (I-g) may also be prepared by reacting an intermediate of formula (XVII) with ammonia and subsequent treatment with isothiocyanate as described in EP-0,293,978 page 12, line 33 to page 13, line 20.
The compounds of formula (I-a) can be converted to compounds of formula (I-b), defined as a compound of formula (I) wherein R6 is hydrogen, by submitting the compounds of formula (I-a) to appropriate reducing conditions, such as, e.g. stirring in acetic acid in the presence of formamide. 
Further, compounds of formula (I-a) can be converted to compounds of formula (I-c) wherein R6 is halo, by reacting the compounds of formula (I-a) with a suitable halogenating agent, such as, e.g. thionyl chloride or phosphorus tribromide. Successively, the compounds of formula (I-c) can be treated with a reagent of formula Hxe2x80x94NR8R9 in a reaction-inert solvent, thereby yielding compounds of formula (I-d). 
A compound of formula (I-f), defined as a compound of formula (I) wherein X is sulfur, may be prepared by reacting the corresponding compound of formula (I-e), defined as a compound of formula (I) wherein X is oxygen, with a reagent like phosphorus pentasulfide or Lawesson""s reagent in a suitable solvent such as, for example, pyridine. 
An intermediate of formula (II-b), defined as an intermediate of formula (II) wherein the dotted line represents a bond, can be prepared by oxidizing an intermediate of formula (II-a), defined as intermediates of formula (II) wherein the dotted line does not represent a bond, following art-known oxidation methods such as, for example, treatment with bromine in an appropriate solvent such as, e.g. bromobenzene, or treatment with iodine in the presence of acetic acid and potassium acetate. 
Said oxidation reaction can give rise to side-products wherein the bivalent radical xe2x80x94Axe2x80x94 is oxidized. For instance, oxidation of intermediates of formula (II-a) wherein xe2x80x94Axe2x80x94 is (a-2) may give intermediates of formula (II-b) wherein xe2x80x94Axe2x80x94 is (a-1).
Intermediates of formula (XVI) wherein R6 is hydrogen, said compounds being represented by formula (XVI-a), can be prepared by reacting intermediates of formula (II) with an appropriate reducing agent such as, e.g. sodium borohydride, in a suitable solvent such as, e.g. methanol. Optionally, intermediates of formula (XVI) may be converted to intermediates of formula (XVII) wherein R6 is hydrogen, said compounds being represented by formula (XVII-a), by treating (XVI-a) with a suitable reagent such as, e.g. methanesulfonyloxy chloride, or a halogenating reagent such as, e.g. POCl3 or SOCl2. 
Intermediates of formula (II-a) can be prepared by reacting intermediates of formula (IV) with intermediates of formula (V) in the presence of polyphosphoric acid (PPA), at a temperature ranging between room temperature and the reflux temperature of the reaction mixture. Optionally said reaction may be performed in a reaction-inert solvent. 
Alternatively, an intermediate of formula (II-a) can be made in a two-step synthesis by cyclizing an intermediate of formula (IV) in the presence of polyphosphoric acid (PPA) and subsequent treating the thus obtained intermediate (VI) with an intermediate of formula (VII) in the presence of PPA. Said two-step synthesis may be conducted in a xe2x80x9cone-potxe2x80x9d synthesis or, if desired, intermediates of formula (VI) may be isolated and purified before reaction with intermediates of formula (V). 
Intermediates of formula (IV) can be prepared by treating intermediates of formula (VIII), wherein X is oxygen or sulfur and Z is hydroxy or halo, with an intermediate of formula (VII) in a reaction-inert solvent such as, e.g. dichloromethane, and in the presence of a base such as, e.g. triethylamine, to pick up the acid liberated during the reaction. 
Intermediates of formula (II-b-1), being intermediates of formula (II-b) wherein X is oxygen and -Axe2x80x2- is a bivalent radical of formula (a-4) or (a-5), can be prepared starting from an intermediate of formula (IX). Said intermediates (IX) are conveniently prepared by protecting the corresponding art-known ketones. Intermediates of formula (IX) are stirred with intermediates of formula (X) in the presence of a base such as sodium hydroxide, in an appropriate solvent, such as an alcohol, e.g. methanol. The thus obtained intermediates of formula (XI) are converted to intermediates of formula (XII) in the presence of a suitable reagent such as, an acid, e.g. TiCl3, in the presence of water; or by hydrogenation under acidic conditions in the presence of a suitable catalyst e.g. platinum on carbon; and by subsequent treatment with acetic anhydride. Intermediates of formula (XII) undergo ring closure in the presence of a base such as, for example, potassium tert-butoxide, and subsequently hydrolysis, yielding intermediates of formula (XIII). After conversion of the methoxy group of intermediates of formula (XVIII) into hydroxy, by treatment with a suitable agent such as, e.g. borontribromide, the intermediates of formula (XIV) are treated with an intermediate of formula (XV), wherein Axe2x80x2 is a bivalent radical of formula (a-4) or (a-5), thereby yielding intermediates of formula (II-b-1). 
The compounds of formula (I) and some of the intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration.
The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereoisomeric forms thereof have valuable pharmacological properties in that they inhibit farnesyl protein transferase (FPTase), as can be evidenced by the results obtained in the pharmacological examples C-1 and C-2.
Furthermore, it is believed that the compounds of formula (I) wherein R5 is a radical of formula (d-2) can also inhibit geranylgeranyltransferase (GGTase).
This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of the invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated ras oncogene; (2) tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant ras activation occurs. Furthermore, it has been suggested in literature that ras oncogenes not only contribute to the growth of of tumors in vivo by a direct effect on tumor cell growth but also indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak. J. et al, Cancer Research, 55, 4575-4580, 1995). Hence, pharmacologically targetting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of a compound of the present invention, to a subject, e.g. a mammal (and more particularly a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated ras oncogene by the administration of an effective amount of the compounds of the present invention. Examples of tumors which may be inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), hematopoietic tumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt""s lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin (e.g. keratoacanthomas), breast carcinoma, kidney carninoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.
This invention may also provide a method for inhibiting proliferative diseases, both benign and malignant, wherein ras proteins are aberrantly activated as a result of oncogenic mutation in genes, i.e. the ras gene itself is not activated by mutation to an oncogenic form, with said inhibition being accomplished by the administration of an effective amount of the compounds described herein, to a subject in need of such a treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes may be inhibited by the compounds of this invention.
Hence, the present invention discloses the compounds of formula (I) for use as a medicine as well as the use of these compounds of formula (I) for the manufacture of a medicament for treating one or more of the above mentioned conditions.
In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, to aid solubility for example, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Those skilled in the art could easily determine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective amount would be from 0.01 mg/kg to 100 mg/kg body weight, and in particular from 0.05 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.5 to 500 mg, and in particular 1 mg to 200 mg of active ingredient per unit dosage form.
The following examples are provided for purposes of illustration.
Experimental Part
Hereinafter xe2x80x9cACNxe2x80x9d means acetonitrile, xe2x80x9cTHFxe2x80x9d means tetrahydrofuran, xe2x80x9cDIPExe2x80x9d means diisopropylether, xe2x80x9cDCMxe2x80x9d means dichloromethane and xe2x80x9cDMFxe2x80x9d means N,N-dimethylformamide.
Of some compounds of formula (I) the absolute stereochemical configuration was not experimentally determined. In those cases the stereochemically isomeric form which was first isolated is designated as xe2x80x9cAxe2x80x9d and the second as xe2x80x9cBxe2x80x9d, without further reference to the actual stereochemical configuration.
A. Preparation of the Intermediates